Micronizing APIs Under Containment
Fully contained micronization of HPAPIs
A key hurdle with APIs is improving their solubility and bioavailability. To meet this challenge, Swiss Group Dec is implementing micronization, the latest technology for reducing the particle size of these potent, biologically active components used in manufacturing medicines.
A micronizing isolator, designed to be CIP
Micronization is one of the very few techniques that can break down particles to within the desired size range. Dec, a producer of powder handling, isolation and containment systems, specializes in spiral jet mill micronization of solid materials in either standard, contained or aseptic format.
This is purposeful since the number of poorly soluble drugs has increased in recent years and only a few of the new drug molecules are characterized with having both solubility and permeability. One of the preferred drug applications is oral drug administration, as per the Biopharmaceutics Classification System (an FDA system that differentiates drugs on the basis of their solubility and permeability).
To achieve the desired pharmacological effect, however, bioavailability and hence the solubility of the drug is of prime importance. According to the Noyes-Whitney equation,* the dissolution rate can be significantly increased by particle size reduction. Reduced particle size is also a crucial factor for the success of inhalation therapies.
Size Reduction Technologies
Spiral jet mill micronization is considered one of the superior milling technologies that produces dry, ultra fine particles (>1–5µm) in a continuous or batch operation under well controllable process conditions and without subjecting the material to thermal stress.
Alternatives like mechanical mills that grind powders by friction, cutting or compressing, such as hammer and pin mills, may create issues, including heat generation and lower size limits of around 40µm. They are also hard to clean and maintain.
Another method of micronization are fluid energy mills. These milling systems function according to the particle collision principle and include the spiral jet mill and the opposed or fluidized-bed jet mill. Opposed jet mills provide two or three opposed gas jets plus a reactive air classifier that controls the particle size above the jets. The powder is fed into the lower portion of the grinding chamber by a gravity feed inlet. The particles collide, decrease and flow up toward the mechanical classifier, which selects the fine particles by negative exhaust pressure and rotating speed into the collection system. Coarser particles return to the milling zone, where they will be reaccelerated for another collision cycle.
One of the main disadvantages, besides abrasion due to mechanical parts, is that fluidized-bed jet mills are difficult to clean depending on the dimension and the number of components. This can lead to potential contamination issues.
State-of-the-art micronizing technology should improve bioavailability through particle size reduction via a controlled process while meeting cGMP regulations, achieving high yields with low energy consumption and allowing for easy scale-up and cleaning.
Spiral Jet Mill Micronization
Dec’s spiral jet mills consist of a flat, cylindrical grinding chamber employing a venturi injector that creates an initial negative pressure to convey the particles into the central chamber at subsonic speed. A series of specially designed nozzles increases the acceleration to supersonic speeds (300 – 500m/s) in a spiral movement. The particle size reduction is generated by the collision of the rotating particles with those entering the milling chamber in a precise and controlled manner using kinetic energy.
Once the particles have achieved the required size, they flow with exhaust gas toward the cyclone where they are separated from the gas by a specially designed filter. The MC DecJet® range of spiral jet mills is used in many industries and features the following advantages for its use in the pharmaceutical industry:
● Made of high-grade materials – AISI type 316L stainless steel or Hastelloy.
● Fast and easy assembly and disassembly with a limited number of components.
● Total absence of screws: smooth and regular surfaces.
● Rapid cleaning and easy validation, CIP/SIP capability.
● Low production loss, virtually no blow-back phenomenon, limited caking of sticky powders.
● Constant process temperature, no heat generation.
● Easy scale-up from development (>0.2g-200g/h) to production (0.5kg– 800kg/h) while maintaining the same narrow particle size distribution.
● Volumetric or gravimetric Pharma execution feeder and various hopper dimensions.
● Custom-designed top or bottom discharge configurations.
● Sanitary rotary valve for product collection.
● Integration of PAT technology, in-line particle size analysis.
● Production-scale units fully automated by PLC.
● Minimized gas/energy consumption.
● ATEX compliant.
The new 4th generation MC DecJet® range has been developed with Computational Fluid Dynamics (CFD) simulation software to analyze “dead” areas within the existing mill geometry, where turbulence causes powder to build up and eventually leads to clogging — and time-consuming and expensive downtime. CFD simulation has allowed the design team to study airflows in jet mills and optimize the internal surfaces and shapes as well as the jet nozzles.
The enhanced internal geometry of the new range has provided increased velocity within the mill chamber and has reduced turbulence within the mill, achieving a finer and tighter particle size distribution.
The R&D model has been specifically designed for small quantities and has obtained excellent results in the area of research. Depending on the quantity to micronize, appropriate feeding systems allow for a constant mass flow when micronizing small quantities. Batches below 2 grams will employ a Venturi suction lance and quantities of 2 g or more are introduced by Dec’s TwinFeeder.
Due to the increasingly potent nature of pharmaceutical ingredients, jet milling isolators meet the containment requirements for both highly active and sterile compounds, guaranteeing operator and product protection.
MC DecJet® 30 unit for batch sizes from 0.2g–50g / h)
Case Study: Micronization inside an Isolator
A recent Dec project consisted of the supply of a special half-suit operated isolation system featuring a through-the-wall design that allows the isolator services, motors, filters, etc., to be executed within the technical area. The isolator ensures containment to a working occupational exposure limit (OEL) of <50ng/m³ time weight averaged (TWA) over an 8-hour period and operates within an ATEX Zone 2/3 G/D IIB T3 classified process room. Given the product toxicity, it was designed to operate under negative pressure to the outside environment with special HEPA filtration on both the exhaust paths and the inlet to the system.
The isolator integrates two milling processes, an MC200 fluid energy mill and a cryogenic version universal mill processing at temperatures down to -20°C, both of which operate on an interchangeable basis. The micronization takes place as a linear process in an area of the chamber’s work surface. Micronized product is conveyed to an integrated cyclone filter allowing contained access to the cyclone filter sleeves. Product discharge from the cyclone is poured into a buffer vessel where it is later conveyed via a Dec powder transfer system to a contained pack-off station.
The grinding chamber is fed by a through-the-wall volumetric feeder. To enable the jet mill to operate as a closed system, the mill venturi feed line is equipped with a closed system with integrated gas purge to the feeder and mill, removing the need for a balance line to the cyclone filter, thus removing additional set-up and cleaning.
The micronizing process operates with nitrogen only and is equipped with an automated inertization system that has an integrated oxygen analyzer. Process interlocks prevent the micronizing system from operating unless a predefined oxygen concentration level has been met.
APIs are automatically fed into the feeder hopper by a powder transfer system drawn from the previous process station. This operation is connected to the PLC which controls the level inside the feeder by employing level sensors.
From there, the product is conveyed into the venturi of the micronizing jet mill, reaching the grinding chamber. Gas is fed into the outer chamber of the jet mill where it is then forced through the jet nozzles spaced around the periphery of the chamber and at tangential angles.
Soon after, nitrogen is discharged into the fluid outlet at the center of the jet mill, which carries the smaller sized particles out of the milling chamber into the cyclone filter for separation, which occurs while the coarse particles are thrown back into the fluid jets for further reduction.
Once the gas/product separation has taken place, the exiting processed gas from the micronizing system will pass through double efficiency HEPA filtration before exiting the isolator. The filters are of the safe change push type and contaminated filters are pushed into the isolator and removed via a rapid transfer port using an endless liner system.
It is important to highlight that the micronizing isolator has been designed with a clean-in-place system that uses a series of spray nozzles and spray guns strategically positioned throughout the plant.
In conclusion, micronization technology is the preferred method to obtain consistent results in size reduction. However, it requires knowledge and expert advice for optimal system design, which must take into account the product properties – a critical factor to the success of any project.
Founded in 1987, Dec Group is a Swiss based leading global provider of powder handling and process containment systems to the pharmaceutical, chemical, food and cosmetic industries.
Dec products offer a high level of safety for both operator and product. Their advanced system concepts, from the standard powder transfer system to highly complex integrated handling and processing equipment, allow clients to increase productivity while respecting current legal requirements. Over the past years, Dec Group has carried out a significant expansion of its activities with the acquisition of specialist companies. The company today develops and provides products classified into the following five technology divisions: Powder Handling, Particle Sizing, Filling Solutions, Containment Solutions and Continuous Processing, thus offering true end-to-end solutions.